The evolution of B-cell clones

Abstract

This chapter identifies three forms of B-cell memory: (a) B blasts which characterize the established stage of the follicular response to TD antigens, (b) recirculating memory B cells, and (c) non-recirculating memory B cells of the marginal zones of the spleen and equivalent areas of other secondary lymphoid organs. The follicular B blasts show sustained proliferation driven by small amounts of antigen bound to FDCs. It is probable that follicular B blasts generate both the recirculating and marginal zone memory cells. This chapter by Gray and Leanderson in this volume cites data which indicate that the recirculating memory pool is not sustained for more than a few weeks in the absence of antigen. Data leading to the same conclusion for marginal zone memory B cells is set out in Sec. 5.1 of this chapter. Marginal zone memory B cells do not appear to move spontaneously to follicles for periodic renewal. They will only leave the marginal zone if a fresh supply of antigen reaches them in that site. Recirculating B cells are able to respond to antigen already held on FDCs. It is not known if they are able to displace B blasts of equivalent affinity for antigen which already occupy antigen-holding sites on FDCs. This could be a mechanism by which B blasts with high antigen affinity produced in one follicle could displace blasts of lower affinity in other follicles. Little is known of the factors which regulate the numbers of marginal zone and recirculating follicular memory B cells. In responses to hapten-protein conjugates, hapten-binding cells may approach 10% of marginal zone B cells but comprise well under 1% of recirculating follicular cells. The numbers of these memory cells do not increase if the recirculating pool of lymphocytes is depleted, indicating that the factors which regulate the number of memory B cells are independent of those which regulate the total size of the recirculating B-cell pool. A depleted peripheral B-cell pool can only be fully reconstituted by recruitment of newly produced virgin B cells. Data cited in Sect. 5.2 support the concept that this recruitment is at least partially independent of antigen-driven B-cell proliferation. Consequently, substantial proportions of the peripheral B-cell pools are likely to be either virgin cells or cells which have been recruited by antigen or anti-idiotype without entering cell cycle. During the first 2-3 weeks following exposure to TD antigen there is massive expansion of B-cell clones within follicles. The proliferative response in each follicle is oligoclonal. The high rate of cell division in follicles is matched by an equally impressive death rate among the B cells generated. Evidence is set out to indicate that this represents an ordered process of selection based on the survival of cells which can be activated by limited supplies of antigen on FDCs. Cells which do not receive this signal within a few hours destroy themselves by apoptosis. This selection process which characterizes the germinal centre stage of the follicular reaction is discussed in detail in Sects. 3.5, 3.6 and 6. It is suggested, on the basis of indirect evidence that centroblasts within germinal centres activate a process which results in hypermutation within their rearranged immunoglobulin V region genes. Extrafollicular B-cell activation appears to be confined to periods immediately following exposure to antigen. The significance of this to the rapid onset of antibody production and the recruitment of both T and B cells into antibody responses is considered in Sect. 3.3. Finally, B-cell activation by TD and tI antigens is compared. Responses to antigens based on pure polysaccharide TI-2 antigens generate little or no memory B cells. They are only able to sustain B blasts in cycle for about 1 month. Responses to these antigens are sustained by continued virgin B-cell recruitment. Evidence is discussed which indicates that TI-2 antigens are only able to activate B cells which have colonized the marginal zones and equivalent areas. Antigens based upon LPS show B-cell recruitment patterns and memory cell formation which is much more closely related to that seen during TD responses.